CA2734397C - Oxadiazole derivatives for the treatment of diabetes - Google Patents

Abstract

The invention relates to a novel oxadiazole derivative such as a compound from the table below (see above table) or a pharmaceutically usable salt, solvate, or steroisomer thereof, or a mixture thereof in any ratio. Said derivatives are kinase inhibitors and may be used to treat illnesses and complaints such as diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonal hypertonia, cardiovascular diseases and kidney diseases, any type of fibrosis, inflammatory processes, tumours, and tumour diseases.

Description

, , OXADIAZOLE DERIVATIVES FOR THE TREATMENT OF DIABETES
BACKGROUND OF THE INVENTION
The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to compounds in which the inhibition, regula-tion and/or modulation of signal transduction by kinases, in particular cell volume-regulated human kinase h-sgk (human serum and glucocorticoid dependent kinase or SGK), plays a role, furthermore to pharmaceutical compositions which comprise these compounds, and to the use of the compounds for the treatment of SGK-induced diseases.
The SGKs with the isoforms SGK-1, SGK-2 and SGK-3 are a serine/threonine protein kinase family (WO 02/17893).
The compounds according to the invention are preferably selective inhibi-tors of SGK-1. They may furthermore be inhibitors of SGK-2 and/or SGK-3.
In detail, the present invention relates to compounds which inhibit, regulate and/or modulate SGK signal transduction, to compositions which comprise these compounds, and to processes for the use thereof for the treatment of SGK-induced diseases and conditions, such as diabetes (for example diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy), obesity, metabolic syndrome (dyslipid-aemia), systemic and pulmonary hypertonia, cardiovascular diseases (for example cardiac fibroses after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, arteriosclerosis) and kidney diseases (for exam-ple glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorder), generally in any type of fibroses and inflammatory

- 2 -processes (for example liver cirrhosis, pulmonary fibrosis, fibrosing pan-creatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring, Alzheimer's dis-ease).
The compounds according to the invention can also inhibit the growth of tumour cells and tumour metastases and are therefore suitable for tumour therapy.
The compounds according to the invention are also used in the treatment of peptic ulcers, in particular in the case of forms triggered by stress.
The compounds according to the invention are furthermore used for the treatment of coagulopathies, such as, for example, dysfibrinogenaemia, hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathy or complex coagulopathies, and also in neuronal excitability, for example epilepsy. The compounds according to the invention can also be employed therapeutically in the treatment of glaucoma or a cataract.
The compounds according to the invention are furthermore used in the treatment of bacterial infections and in anti-infection therapy. The com-pounds according to the invention can also be employed therapeutically for increasing learning ability and attention. In addition, the compounds according to the invention counter cell ageing and stress and thus increase life expectancy and fitness in the elderly.
The compounds according to the invention are furthermore used in the treatment of tin nitus.
The identification of small compounds which specifically inhibit, regulate and/or modulate SGK signal transduction is therefore desirable and an aim of the present invention.
It has been found that the compounds according to the invention and salts thereof have very valuable pharmacological properties while being well tol-erated.

- 3 -In particular, they exhibit SGK-inhibiting properties.
The compounds according to the invention furthermore exhibit activity towards other kinases, such as Aurora-B, MAPK2, MSK1, PRK2, DYRK1, CHK2, GSK3-beta, PKB (AKT), ROCKII or S6K1, Limk1, TGF-beta, MAPK8, PLK1, PDK1, MKK1, SAPK3, SAPK4, MAPKAP-K1-alpha, MAPKAP-K1-beta, AMPK, CDK2/cyclin A, PKA, PIM-2, MNK-1, MARK3, HIPK2, PIM1, PIM3, BRSK2, MELK, FGFR1 or EphA2,.
Heterocyclic compounds having an inhibitory action on GSK3-beta are described, for example, in WO 2008/078196.
The compounds are useful for the treatment of neurodegenerative dis-eases, such as, for example, Parkinson's, tauopathies, such as, for exam-ple, Alzheimer's disease, corticobasal degeneration, Pick's disease, Wil-son's disease, Huntington's disease, furthermore vascular dementia, acute strokes, peripheral neuropathies, retinopathy or glaucoma, furthermore manic-depressive diseases. Through the inhibition of GSK3-beta, the compounds can also be used for the treatment of cancer and tumour dis-eases.
The compounds according to the invention can in addition also be used for the treatment of autoimmune diseases, inflammatory and proliferative dis-eases, AIDS, asthma, rhinitis and Crohn's disease.
The present invention therefore relates to compounds according to the invention as medicaments and/or medicament active ingredients in the treatment and/or prophylaxis of the said diseases and to the use of com-pounds according to the invention for the preparation of a pharmaceutical for the treatment and/or prophylaxis of the said diseases and also to a process for the treatment of the said diseases which comprises the admini-stration of one or more compounds according to the invention to a patient in need of such an administration.

- 4 The host or patient may belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model for the treatment of a human disease.
For identification of a signal transduction pathway and for detection of interactions between various signal transduction pathways, various scien-tists have developed suitable models or model systems, for example cell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (for example White et al., Oncogene, 2001, 20, 7064-7072). For the determination of certain stages in the signal trans-duction cascade, interacting compounds can be utilised in order to modu-late the signal (for example Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in ani-mals and/or cell culture models or in the clinical diseases mentioned in this application.
Measurement of the kinase activity is a technique which is well known to the person skilled in the art. Generic test systems for the determination of the kinase activity using substrates, for example histone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin protein, are described in the literature (for example Campos-Gonzalez, R.
and Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, page 14535).
Various assay systems are available for identification of kinase inhibitors.
In the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screen-ing, 2002, 7, 11-19) and the flashplate assay, the radioactive phosphoryla-tion of a protein or peptide as substrate is measured using yATP. In the

5 presence of an inhibitory compound, a reduced radioactive signal, or none at all, can be detected. Furthermore, homogeneous time-resolved fluores-cence resonance energy transfer (HTR-FRET) and fluorescence polarisa-tion (FP) technologies are useful as assay methods (Sills et al., J. of Bio-molecular Screening, 2002, 191-214).
Other non-radioactive ELISA assay methods use specific phospho-anti-bodies (phospho-ABs). The phospho-AB only binds the phosphorylated substrate. This binding can be detected by chemoluminescence using a second peroxidase-conjugated antisheep antibody (Ross et al., Biochem.
J., 2002, 366, 977-981).
It can be shown that the compounds according to the invention have an antiproliferative action in vivo in a xenotransplant tumour model. The com-pounds according to the invention are administered to a patient having a hyperproliferative disease, for example to inhibit tumour growth, to reduce inflammation associated with a lymphoproliferative disease, to inhibit trans-plant rejection or neurological damage due to tissue repair, etc. The pre-sent compounds are suitable for prophylactic or therapeutic purposes. As used herein, the term "treatment" is used to refer to both prevention of dis-eases and treatment of pre-existing conditions. The prevention of prolif-eration is achieved by administration of the compounds according to the invention prior to the development of overt disease, for example to prevent the tumour growth, prevent metastatic growth, diminish restenosis associ-ated with cardiovascular surgery, etc. Alternatively, the compounds are used for the treatment of ongoing diseases by stabilising or improving the clinical symptoms of the patient.
The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in-vitro testing. Typically, a culture of the cell is combined with a compound according to the inven-tion at various concentrations for a period of time which is sufficient to s WO 2010/020305 allow the active agents to induce cell death or to inhibit migration, usually between about one hour and one week. In vitro testing can be carried out using cultivated cells from a biopsy sample. The viable cells remaining after the treatment are then counted.
The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue, while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
PRIOR ART
Other aminoaryl compounds are described as tyrosine kinase inhibitors in WO 2006/064375 A2 for the treatment of cancer, allergic and inflammatory diseases, rheumatoid arthritis and autoimmune diseases.
Other oxadiazole derivatives are disclosed in WO 2006/064189 Al for the treatment of diabetes mellitus and obesity.
Other heterocyclic derivatives are described in WO 2006/024034 Al, inter alia for the treatment of cancer and inflammation.
lndoles and other heterocyclic derivatives are disclosed as kinase inhibi-tors in US 2005/250829.
Other heterocyclic oxadiazole derivatives are known from WO 2002/72549 Al.
WO 00/62781 describes the use of medicaments comprising inhibitors of cell volume-regulated human kinase H-SGK.
Heterocyclic indazole derivatives for the treatment of diabetes and/or can-cer diseases are known from WO 2006/044860 and WO 2005056550.
US 2005090529 discloses indazole derivatives for the treatment of diabetic retinopathy.

Indazole derivatives for the treatment of tumours are disclosed in WO 2005000813, those for the treatment of cardiovascular diseases are disclosed in WO 2004060318.
Other heterocyclic compounds for the treatment of tumours are known from W02004052280.
Furthermore, other heterocyclic compounds for the treatment of psychotic diseases are disclosed in EP 328200.
Indazole derivatives are described as protein kinase inhibitors in WO 03/064397.
In Bioorganic & Medicinal Chemistry Letters 13 (2003) 3059-3062, J. Witherington et al. describes the preparation of indazole derivatives.
Indazole derivatives are described as kinase inhibitors in WO 2003097610.
Indazole derivatives are disclosed as GSK-3 inhibitors in WO 2003051847.
Triazolopyridazine derivatives are described as Met kinase inhibitors in WO 2007/064797, WO 2007/075567, WO 2007/138472, WO
2008/008539, WO 2008/051805.
The use of kinase inhibitors in anti-infection therapy is described by C.Doerig in Cell. Mol. Biol. Lett. Vol.8, No. 2A, 2003, 524-525.
The use of kinase inhibitors in obesity is described by N.Perrotti in J. Biol.

Chem. 2001, March 23; 276(12):9406-9412.
The following references suggest and/or describe the use of SGK inhibi-tors in disease treatment:
1: Chung EJ, Sung YK, Farooq M, Kim Y, Im S, Tak VVY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells. 2002;14:382-7.
2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1(SGK-1). J Biol Chem. 2002;277:43064-70.

, ' - 8 -3: Fillon S, Klingel K, Warntges S, Sauter M, Gabrysch S, Pestel S, Tan-neur V, Waldegger S, Zipfel A, Viebahn R, Haussinger D, Broer S, Kandolf R, Lang F. Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis. Cell Physiol Biochem. 2002;12:47-54.
4: Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOX03a). Mol Cell Biol 2001;21:952-65 5: Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Gluco-corticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem.
2001;276:16649-54.

6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Hon-kanen RE. SerfThr protein phosphatase type 5 (PP5) is a negative regu-lator of glucocorticoid receptor-mediated growth arrest. Biochemistry.
1999;38:8849-57.

7: Buse P, Tran SH, Luther E, Phu PT, Aponte GW, Firestone GL. Cell cycle and hormonal control of nuclear-cytoplasmic localization of the serum- and glucocorticoid-inducible protein kinase, Sgk, in mammary tumor cells. A novel convergence point of anti-proliferative and proliferative cell signalling pathways. J Biol Chem. 1999;274:7253-63.

8: M. Hertweck, C. GObel, R. Baumeister: C.elegans SGK-1 is the critical component in the Akt/PKB Kinase complex to control stress response and life span. Developmental Cell, Vol. 6, 577-588, April, 2004.

, WO 2010/020305 PCT/EP2009/004992

- 9 -SUMMARY OF THE INVENTION
The invention relates to compounds of the formula 1 N
Rix \ Y------I
N \
/ \ /
R

in which R, R' each, independently of one another, denote H, A, L-Ar or L-Het, Y N, CH or CR11, X1, X2, X3 each, independently of one another, denote H, Hal, A or Ar, L is absent or denotes CR7R8, CR7R8CR9R19, CR7R8C(0R9)R19, OCR7R8, OCR7R8CR9R19, CR7R80, CR7R8CR9R190 or CR7R8S02, R7, R8, R9, R19 each, independently of one another, denote H or A, R11 denotes alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F, A, A' each, independently of one another, denote alkyl having 1-10 C
atoms which is unsubstituted or mono-, di- or trisubstituted by R3, =S, =NR7 and/or =0 (carbonyl oxygen) and in which one, two or three CH2 groups may be replaced by 0, S, SO, SO2, NH, NR11 and/or by ¨CH=CH- groups and/or, in addition, 1-7 H atoms may be replaced by F and/or Cl, or cyclic alkyl having 3-7 C atoms, Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubsti-tuted or mono-, di-, tri-or tetrasubstituted by A, Hal, OH, OA, Ar', OAr', Het, Het, SH, SA, SAr', SHet, NH2, NHA, NAA', NHAr, N(Ar1)2, NHHet, N(Het)2, NAAr, NAHet, SOA, SOAr', SOHet, SO2A, SO2Ar, SO2Het, NO2, CN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NACOA, NHCONH2, NHCONHA, NHCONA2, , - 10 -NHSO2A, NASO2A, CHO, COA, COAr', COHet, SO3H, SO2NH2, SO2NHAr', SO2N(Ar')2, SO2NHHet and/or SO2N(Het)2, Het denotes a mono- or bicyclic saturated, unsaturated or aromatic het-erocycle having 1 to 4 N, 0 and/or S atoms, which may be mono-, di- or trisubstituted by A, Hal, OH, OA, Ar, OAr, Het', 0Hef, SH, SA, SAr', SHef, NH2, NHA, NAA', NHAr', N(Ar1)2, NHHet', N(Hef)2, NAAr', NAHet', SOA, SOAr', SOHet', SO2A, SO2Ar, SO2Het', NO2, CN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NACOA, NHCONH2, NHCONHA, NHCONA2, NHSO2A, NASO2A, CHO, COA, COAr', COHet', SO3H, SO2NH2, SO2NHAr', SO2N(Ar')2, SO2NHHet' or SO2N(Het1)2, =S, =NR7 and/or =0 (carbonyl oxygen), Ar' denotes phenyl which is unsubstituted or mono-, di-, tri-or tetra-substituted by A, Hal, OH, OA, 0-phenyl, SH, SA, NH2, NHA, NAA', NH-phenyl, SOA, SO-phenyl, SO2A, S02-phenyl, NO2, CN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NACOA, NHCONH2, NHCONHA, NHCONA2, NHSO2A, NASO2A, CHO, COA, CO-phenyl, SO3H, SO2NH2, SO2NH-phenyl and/or SO2N(pheny1)2, Het' denotes a mono- or bicyclic saturated, unsaturated or aromatic het-erocycle having 1 to 4 N, 0 and/or S atoms, which may be mono-, di- or trisubstituted by A, Hal, OH, OA, NH2, NHA, NAA', SOA, SOAr', SO2A, SO2Ar, NO2, CN, COOH, COOA, CONH2, CONHA, CONA2, NHCOA, NACOA, NHCONH2, NHCONHA, NHCONA2, NHSO2A, NASO2A, CHO, COA, COAr', SO3H, SO2NH2, SO2NHAr, SO2N(Ar')2, =S, =NR7 and/or =0 (carbonyl oxygen), Hal denotes F, Cl, Br or I, and pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
The invention relates to the compounds of the formula I and salts thereof and to a process for the preparation of compounds of the formula I and pharmaceutically usable salts and stereoisomers thereof, characterised in that a) a compound of the formula II

H
11.1 R' HO __________________________ /

in which X1, X2, X3, R, R' and Y have the meanings indicated above, is cyclised, or b) a compound of the formula Ill z N¨NH2 Ill HO __________________________ /

in which X1, X2, X3 have the meanings indicated above, is reacted with a cyanogen halide, or c) a compound of the formula la in which R1 denotes an alkyl radical having 1, 2, 3 or 4 C atoms N¨N
R' sc) la XI

is converted into a compound of the formula I by ether cleavage, and/or a base or acid of the formula I is converted into one of its salts.
The compounds of the formula I are also taken to mean the hydrates and solvates of these compounds, furthermore pharmaceutically usable deriva-tives.
The invention also relates to the stereoisomers (E, Z isomers) and the hydrates and solvates of these compounds. Solvates of the compounds are taken to mean adductions of inert solvent molecules onto the com-pounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
Pharmaceutically usable derivatives are taken to mean, for example, the salts of the compounds according to the invention and also so-called pro-drug compounds.
Prod rug derivatives are taken to mean compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligo-peptides and which are rapidly cleaved in the organism to form the active compounds according to the invention.
These also include biodegradable polymer derivatives of the compounds according to the invention, as is described, for example, in Int. J. Pharm.
115, 61-67 (1995).

, . - 13 -The expression "effective amount" means the amount of a medicament or pharmaceutical active ingredient which causes a biological or medical response which is sought or aimed at, for example by a researcher or phy-sician, in a tissue, system, animal or human.
In addition, the expression "therapeutically effective amount" means an amount which, compared with a corresponding subject who has not received this amount, has the following consequence:
improved treatment, healing, prevention or elimination of a disease, syn-drome, condition, state, disorder or side effects or also the reduction in the progress of a disease, condition or disorder.
The expression "therapeutically effective amount" also encompasses the amounts which are effective for increasing normal physiological function.
The invention also relates to mixtures of the compounds of the formula I
according to the invention, for example mixtures of two diastereomers or enantiomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.
These are particularly preferably mixtures of stereoisomeric compounds, in particular the compounds according to the invention are in the form of the racemate.
For all radicals which occur more than once, their meanings are independ-ent of one another.
Above and below, the radicals and parameters R, R', Y, X1, X2 and X3 have the meanings indicated for the formula I, unless expressly indicated other-wise.
A, A' denote, in each case independently of one another, alkyl, is un-branched (linear) or branched, and has 1, 2, 3,4, 5, 6, 7, 8, 8, 9 or 10 C
atoms. A, A' preferably denote methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-, , - 14 -methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3- , 2,2- , 2,3-or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.
A, A' very particularly preferably denote alkyl having 1, 2, 3, 4, 5 or 6 C
atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoro-ethyl.
A particularly preferably denotes alkyl having 1-10 C atoms, in which 1-7 H
atoms may be replaced by F and/or Cl.
R preferably denotes H.
R' preferably denotes H or L-Ar.
L preferably denotes L CR7R8 or CR7R8CR9R19. L particularly preferably denotes CH2, CH2CH2 or CH(CH3).
X1, X2, X3 preferably, in each case independently of one another, denote H, Hal or A.
R7, R8, R9, R10 preferably, in each case independently of one another, denote H or R11.
R7, R9, R9, R19 particularly preferably, in each case independently of one another, denote H or CH3.
Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butyl-phenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methyl-aminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxy-phenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m-or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-dimethylaminocarbonyI)-phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)-phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-(nnethylsulfonamido)phenyl, o-, m- or p-(methyl-' W02010/020305 sulfonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m-or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonyl-phenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m-or p-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5-or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di-chloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-meth-oxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Ar preferably denotes phenyl which is unsubstituted or mono-, di-, tri- or tetrasubstituted by A, Hal, OH and/or OA, such as, for example, o-, m- or p-methoxyphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluorophenyl or 3-chloro-4-fluorophenyl.
Ar' preferably denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butyl-phenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methyl-aminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxy-phenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, 0-, m-or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-dimethylaminocarbonyI)-phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)-phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-= - 16 -chlorophenyl, o-, m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methyl-sulfonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m-or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonyl-phenyl, o-, m- or p-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m-or p-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5-or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di-chloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-meth-oxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethy1-4-chlorophenyl.
Irrespective of further substitutions, Het denotes, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazoly1, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further-more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, = -17-6-, 7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxo1-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-y1 or 2,1,3-benzoxa-diazol-5-yl.
The heterocyclic radicals may also be partially or fully hydrogenated.
Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-di-hydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2-or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-mor-pholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4-or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimi-dinyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy-phenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-di-hydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.
Het preferably denotes a monocyclic aromatic heterocycle having 1 to 4 N, 0 and/or S atoms.
Het particularly preferably denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazo-lyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-tri-azol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxa-diazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl.

, Het very particularly preferably denotes pyrrolyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl.
Het' preferably denotes a monocyclic saturated, unsaturated or aromatic heterocycle having 1 to 2 N and/or 0 atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and/or OA.
In a further embodiment, Het' particularly preferably denotes furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrroli-dinyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, Hal, OH and/or OA.
The compounds of the formula I can have one or more centres of chirality and can therefore occur in various stereoisomeric forms. The formula I en-compasses all these forms.
Accordingly, the invention relates, in particular, to compounds of the for-mula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulae la to II, which conform to the for-mula I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which in la R denotes H;
in lb R' denotes H or L-Ar;
in lc L denotes CR7R8 or CR7R8CR9R10;
in Id L denotes CH2, CH2CH2 or CH(CH3);

= WO 2010/020305 , in le X1, X2, X3 each, independently of one another, denote H, Hal or A;
in If A denotes alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or Cl;
in Ig Ar denotes phenyl which is unsubstituted or mono-, di-, tri-or tetrasubstituted by A, Hal, OH and/or OA;
in lh Het denotes a nnonocyclic aromatic heterocycle having 1 to 4 N, 0 and/or S atoms;
in Ii Het denotes 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3-or 4-pyridazinyl or pyrazinyl;
in lj R7, R8, R9, R10 each, independently of one another, denote H or R11;
in lk R7, R8, R9, R19 each, independently of one another, denote H or CH3;
in II R denotes H, R' denotes H or L-Ar, Y denotes N, CH or CR11, xl, x2, x3 each, independently of one another, denote H, Hal or A, L denotes CR7R8 or CR7R8CR9R10 , R7, R8, R9, R10 each, independently of one another, denote H or R11, R11 denotes alkyl having 1-6 C atoms, in which 1-5 H atoms may be replaced by F, A denotes alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or Cl, Ar denotes phenyl which is unsubstituted or mono-, di-, tri-or tetrasubstituted by A, Hal, OH and/or OA, Hal denotes F, Cl, Br or I;
and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.
An aspect of the invention relates to a compound which is - 20a -No. Structural formula and/or name "Al" 3-Ethy1-4-[5-(3-fluorobenzylamino)-113,4-oxadiazol-2-y1}-2-methylphenol 3-Ethy1-445-(3-methoxybenzylamino)-1,3,4-oxadiazol-2-y1]-2-methylphenol 3-Ethyl-4-{5-[(R)-1-(3-methoxyphenyl)ethylamino]- 1,3,4-oxadiazol-2-y1}-2-methylphenol =
4-(5-Amino-1,3,4-oxadiazol-2-y0-3-ethyl-2-methyl-phenol "A10" 645-(3-Fluorobenzylamino)-1,3,4-oxadiazol-2-y1]-pyridin-3-ol "A11" 2,3-Difluoro-4-[5-(3-fluorobenzylamino)-1,3,4-oxa-diazol-2-yl]phenol or pharmaceutically usable salt, solvate, or steroisomer thereof, or a mixture thereof in any ratio.
The compounds according to the invention and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use may also be made here of variants known per se which are not mentioned here in greater detail.
If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds according to the invention.

= - 20b -The starting compounds are generally known. If they are novel, however, they can be prepared by methods known per se.

, , - 21 -Compounds of the formula I can preferably be obtained by cyclising com-pounds of the formula II. The cyclisation is preferably carried out with addi-tion of a mercury salt in an inert solvent.
The mercury salt is particularly preferably mercury (II) acetate.
Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -300 and 140 , nor-mally between 00 and 100 , in particular between about 60 and about 90 .
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petro-leum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as tri-chloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or di-chloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetra-hydrofuran (THE) or dioxane; glycol ethers, such as ethylene glycol mono-methyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMS0); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene;
esters, such as ethyl acetate, or mixtures of the said solvents.
Methanol or ethanol is particularly preferred.
Compounds of the formula I can furthermore preferably be obtained by react-ing compounds of the formula Ill with a cyanogen halide, preferably BrCN.
The reaction is carried out in an inert solvent, as indicated above, preferably in water and/or DMF.
Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -30 and 140 , nor-mally between 0 and 100 , in particular between about 15 and about 70 .
The reaction is generally carried out in the presence of an acid-binding agent, preferably an alkali or alkaline-earth metal hydroxide, carbonate or bicarbon-ate or another salt of a weak acid of the alkali or alkaline-earth metals, prefer-ably of potassium, sodium, calcium or caesium. The addition of an organic base, such as triethylamine, dimethylaniline, pyridine or quinoline, may also be favourable.
Compounds of the formula I can furthermore preferably be obtained by cleav-ing the ether in compounds of the formula la.
In the compounds of the formula la, R1 preferably denotes alkyl having 1, 2, 3 or 4 C atoms.
The cleavage of an ether is carried out under methods as are known to the person skilled in the art.
A standard method of ether cleavage, for example of a methyl ether, is the use of boron tribromide.
Hydrogenolytically removable groups, for example the cleavage of a benzyl ether, can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palla-dium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 1000 and pres-sures between about 1 and 200 bar, preferably at 20-30 and 1-10 bar.
Esters can be saponified, for example, using acetic acid or using NaOH or KOH in water, water/THF or water/dioxane, at temperatures between 0 and 100 .
Pharmaceutical salts and other forms The said compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically accept-able salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. Pharmaceutically acceptable , salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I contains a car-boxyl group, one of its suitable salts can be formed by reacting the com-pound with a suitable base to give the corresponding base-addition salt.
Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methyl-glutamine. The aluminium salts of the compounds of the formula I are like-wise included. In the case of certain compounds of the formula I, acid-addition salts can be formed by treating these compounds with pharma-ceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoro-acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascor-bate and the like. Accordingly, pharmaceutically acceptable acid-addition salts of the compounds of the formula I include the following: acetate, adi-pate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, diglu-conate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane-sulfonate, fumarate, galacterate (from mucic acid), galacturonate, gluco-heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydro-bromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphos-phate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmo-. - 24 -ate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a restriction.
Furthermore, the base salts of the compounds according to the invention include aluminium, ammonium, calcium, copper, iron(III), iron(II), lithium, magnesium, manganese(III), manganese(II), potassium, sodium and zinc salts, but this is not intended to represent a restriction. Of the above-men-tioned salts, preference is given to ammonium; the alkali metal salts so-dium and potassium, and the alkaline-earth metal salts calcium and mag-nesium. Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of pri-mary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, di-ethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoetha-nol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lido-caine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanol-amine, triethylamine, trimethylamine, tripropylamine and tris(hydroxy-methyl)methylamine (tromethamine), but this is not intended to represent a restriction.
Compounds of the present invention which contain basic nitrogen-contain-ing groups can be quaternised using agents such as (C1-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(C1-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10-C18)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(C1-C4)alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-solu-ble compounds according to the invention can be prepared using such salts.
The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisucci-nate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and trometh-amine, but this is not intended to represent a restriction.
The acid-addition salts of basic compounds of the formula I are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner.
The free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner. The free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts other-wise correspond to the respective free base forms thereof.
As mentioned, the pharmaceutically acceptable base-addition salts of the compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline-earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, dietha-nolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
The base-addition salts of acidic compounds according to the invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conven-tional manner. The free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional man-ner. The free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solu-bility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof.
If a compound according to the invention contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, di-phosphate, disodium and trihydrochloride, but this is not intended to repre-sent a restriction.
With regard to that stated above, it can be seen that the expression "phar-maceutically acceptable salt" in the present connection is taken to mean an active ingredient which comprises a compound of the formula I in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
Compounds of the formula I according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantio-meric forms. They can therefore exist in racemic or in optically active form.
Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the interme-diates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other deriva-tives of carbohydrates or chirally derivatised methacrylate polymers immo-bilised on silica gel). Suitable eluents for this purpose are aqueous or alco-holic solvent mixtures, such as, for example, hexane/isopropanol/aceto-nitrile, for example in the ratio 82:15:3.
The invention furthermore relates to the use of the compounds and/or physiologically acceptable salts thereof for the preparation of a medica-ment (pharmaceutical composition), in particular by non-chemical meth-ods. They can be converted into a suitable dosage form here together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if desired, in combination with one or more further active ingredients.
The invention furthermore relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.
Pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, prefer-ably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a com-pound according to the invention, depending on the condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process which is generally known in the pharmaceutical art.
Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublin-gual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).
Pharmaceutical formulations adapted for oral administration can be admin-istered as separate units, such as, for example, capsules or tablets; pow-ders or granules; solutions or suspensions in aqueous or non-aqueous liq-uids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for , - 29 -example, an edible carbohydrate, such as, for example, starch or mannitol.
A flavour, preservative, dispersant and dye may likewise be present.
Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, cal-cium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disinteg rant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medica-ment after the capsule has been taken.
In addition, if desired or necessary, suitable binders, lubricants and disinte-grants as well as dyes can likewise be incorporated into the mixture. Suit-able binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and syn-thetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubri-cants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granu-lating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for exam-ple, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accel-erator, such as, for example, a quaternary salt, and/or an absorbent, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The compounds according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
Oral liquids, such as, for example, solution, syrups and elixirs, can be pre-pared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be for-mulated by dispersion of the compound in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.
The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.

, - 31 -The compounds according to the invention and salts thereof can also be administered in the form of liposome delivery systems, such as, for exam-ple, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.
The compounds according to the invention and the salts can also be deliv-ered using monoclonal antibodies as individual carriers to which the corn-pound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted medicament carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmeth-acrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, poly-orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compounds adapted for topical administration can be for-mulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient .

can be employed either with a paraffinic or a water-miscible cream base.
Alternatively, the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.
Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.
Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose.
Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.
Pharmaceutical formulations adapted for administration by inhalation en-compass finely particulate dusts or mists, which can be generated by vari-ous types of pressurised dispensers with aerosols, nebulisers or insuffla-tors.
Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

. - 33 -Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxi-dants, buffers, bacteriostatics and solutes, by means of which the formula-tion is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise sus-pension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, imme-diately before use is necessary.
Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.
It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, for-mulations which are suitable for oral administration may comprise flavours.
A therapeutically effective amount of a compound of the present invention depends on a number of factors, including, for example, the age and weight of the human or animal, the precise condition which requires treat-ment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet.
However, an effective amount of a compound according to the invention for the treatment is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or more usually in a series of part-doses (such as, for example) two, three, four, five or six) per day, so that the total daily dose is the same.
An effective amount of a salt or solvate or of a physiologically functional . WO 2010/020305 derivative thereof can be determined as the fraction of the effective amount of the compound according to the invention per se. It can be assumed that similar doses are suitable for the treatment of other condi-tions mentioned above.
The invention furthermore relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.
The invention also relates to a set (kit) consisting of separate packs of (a) an effective amount of a compound according to the invention and/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
The set comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The set may, for example, comprise separate am-poules, each containing an effective amount of a compound according to the invention and/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active ingredient in dis-solved or lyophilised form. .
USE
The present compounds are suitable as pharmaceutical active ingredients for mammals, in particular for humans, in the treatment of SGK-induced diseases.

The invention thus relates to the use of compounds according to formula 1, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of kinase signal transduction plays a role.
Preference is given here to SGK.
Preference is given to the use of compounds according to formula 1, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment of diseases which are influenced by inhibition of SGK by the compounds according to formula I.
The present invention encompasses the use of the compounds according to formula I according to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of diabetes (for example diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopa-thy), obesity, metabolic syndrome (dyslipidaemia), systemic and pulmo-nary hypertonia, cardiovascular diseases (for example cardiac fibroses after myocardial infarction, cardiac hypertrophy and cardiac insufficiency, arteriosclerosis) and kidney diseases (for example glomerulosclerosis, nephrosclerosis, nephritis, nephropathy, electrolyte excretion disorder), generally in any type of fibroses and inflammatory processes (for example liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclero-dermatitis, cystic fibrosis, scarring, Alzheimer's disease).
The compounds according to the invention can also inhibit the growth of cancer, tumour cells and tumour metastases and are therefore suitable for tumour therapy.

The compounds according to the invention are furthermore used for the treatment of coagulopathies, such as, for example, dysfibrinogenaemia, hypoproconvertinaemia, haemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, hyperfibrinolysis, immuno-coagulopathy or complex coagulopathies, and also in neuronal excitability, for example epilepsy. The compounds according to the invention can also be employed therapeutically in the treatment of glaucoma or a cataract.
The compounds according to the invention are furthermore used in the treatment of bacterial infections and in anti-infection therapy. The com-pounds according to the invention can also be employed therapeutically for increasing learning ability and attention.
Preference is given to the use of compounds according to formula I, and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment or prevention of diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular dis-eases and kidney diseases, generally in any type of fibroses and inflam-matory processes, cancer, tumour cells, tumour metastases, coagulo-pathies, neuronal excitability, glaucoma, cataract, bacterial infections and in anti-infection therapy, for increasing learning ability and attention, and for the treatment and prophylaxis of cell ageing and stress.
Diabetes is preferably diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy.
Cardiovascular diseases are preferably cardiac fibroses after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and arteriosclerosis.
Kidney diseases are preferably glomerulosclerosis, nephrosclerosis, neph-ritis, nephropathy and electrolyte excretion disorder.

= WO

Fibroses and inflammatory processes are preferably liver cirrhosis, pulmo-nary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibro-sis, scarring, Alzheimer's disease.
ASSAYS
The compounds according to the invention described in the examples were tested by the assays described below and were found to have kinase inhibitory activity. Other assays are known from the literature and could readily be performed by the person skilled in the art (see, for example, Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem.
274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538- 549).
The inhibition of SGK1 protein kinase can be determined in the filter bind-ing method.
Above and below, all temperatures are indicated in C. In the following examples, "conventional work-up" means: if necessary, water is added, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl ace-tate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation. Rf values on silica gel; eluent: ethyl acetate/methanol 9:1.
Mass spectrometry (MS): El (electron impact ionisation) M+
FAB (fast atom bombardment) (M+H)+
ESI (electrospray ionisation) (M+H)+ (unless indicated otherwise) HPLC method A (polar): Hewlett Packard HP 1100 series system with the following fea-tures: ion source: ES (positive mode); scan: 100-1000 m/e; fragmentation voltage: 60 V; gas temperature: 300 C, DAD: 220 nm.
Column: Chromolith SpeedROD RP-18e, 50-4.6 Flow rate: 2.4 ml/min.
The splitter used reduced the flow rate after the DAD to 0.75 ml/min for the MS.
Solvent A: water +0.01% of TFA
Solvent B: acetonitrile + 0.08% of TFA
Gradient:
0.0 min 4% of B
2.6 min 100% of B
3.3 min 100% of B
B:
Column: Chromolith SpeedROD RP-18e, 50-4.6 Flow rate 2.4 ml/min Solvent A: water +0.1 /0 of TFA
Solvent B: acetonitrile + 0.1% of TFA
Gradient:
0.0 min 4% of B
2.6 min 100% of B
3.3 min 100% of B
HPLC-MS : Esil.rod.m I polar.m / unpolar.m method Column : Chromolith Speed Rod RP 18e 50-4.6 mm . - 39 -Flow rate : 2.4 ml/min Buffer A : 0.01% of TFA / water Buffer B : 0.008% of TFA / acetonitrile Wavelength : 220 nm Gradient : 0.0-2.8min 20%-100% of buffer B; 2.8-3.3min 100%
of buffer B;
Esil.rod.m 3.3-3.4 min 100%-20% of buffer B; 3.4-3.8min 20%
of buffer B
Gradient : 0.0-3.0min 5%-100% of buffer B; 3.0-3.5min 100% of buffer B;
polar.m 3.5-3.6 min 100%-5% of buffer B; 3.6-3.8min 20%
of buffer B
Gradient : 0.0-2.5min 40%-90% of buffer B; 2.5-3.8min 90%
of buffer B;
unpolar.m 3.8-3.9 min 90% of buffer B : 3.9-4.1min 90%-40%
of buffer B
Abbreviations:
DCM = dichloromethane EA = ethyl acetate PE = petroleum ether RT = room temperature DAPECI = N-(3-dimethylaminopropyI)-N'-ethylcarbodiimide hydrochloride DMF = dimethylformamide HOBT = 1-hydroxybenzotriazole NCS = N-chlorosuccinimide TEA = trifluoroacetic acid Synthesis Examples Method 1: (compounds "Al", "A2", "A3") = -40-0 \ 0 0 411/ 0 lik HO o¨

OH ----". 0 ¨
l = 0 N¨NH2 ______________________________________________ ik 0 N¨N . H
N
H
S
R
0 1,1-..N
Hg(II), Me0H, 80 C HO / I
O'NN
1-i O
R
Preparation of 3-ethy1-4-15-(3-fluorobenzylamino)-1,3,4-oxadiazol-2-y11-2-methylphenol ("Al") Step 1: Methyl 2-ethyl-4-methoxy-3-methylbenzoate:
5.0 g of 2-ethyl-4-methoxy-3-nnethylbenzoic acid are refluxed with 0.5 ml of conc. sulfuric acid and 50 ml of methanol in a round-bottomed flask for 2 days. The solvent is distilled off, 100 ml of water are added to the residue, and the precipitated solid is filtered off with suction and dried, giving 5.2 g of methyl 2-ethyl-4-methoxy-3-methylbenzoate (quant); MS-FAB (M+H+) =
209.1; Rf (polar method): 2.46 min.
Step 2: Methyl 2-ethy1-4-hydroxy-3-methylbenzoate:
2.0 g of methyl 2-ethyl-4-methoxy-3-methylbenzoate are dissolved in 50 ml of DCM in a 100 ml round-bottomed flask, and BBr3 is carefully added dropwise at 0 C. The mixture is left to stir at RT for 4 hours. The solvent is distilled off in vacuo, methanol is carefully added to the residue at 0 C, and the mixture is evaporated again in a rotary evaporator. This operation is repeated a further twice, giving 1.88 g of methyl 2-ethy1-4-hydroxy-3-methylbenzoate as oil, which is employed for the next step without further purification; MS-FAB (M+H+) = 195.2; Rf (polar method): 1.96 min.
Step 3: 2-Ethyl-4-hydroxy-3-methvlbenzohydrazide:
1 ml of butanol and 4.5 ml of hydrazine hydrate are added to 1.88 g of methyl 2-ethyl-4-hydroxy-3-methylbenzoate in a screw-lid vial, and the mixture is stirred at 100 C until the hydrazide formation is complete. The cooled reaction mixture is poured onto water, the precipitate is filtered off with suction and dried. Purification by recrystallisation from water/l-propa-nol gives 1.28 g of 2-ethyl-4-hydroxy-3-methylbenzohydrazide as colour-less crystals (68%); MS-FAB (M+H+) = 1.95.1; Rf (polar method): 0.99 min.
Step 4: Coupling to 1-fluoro-3-(isothiocyanatornethyl)benzene 194 mg of 2-ethyl-4-hydroxy-3-methylbenzohydrazide and 167 mg of 1-fluoro-3-(isothiocyanatomethyl)benzene are stirred overnight at 50 C in 10 of DCM in a screw-lid vial. The reaction mixture is cooled, the deposited crystals are filtered off with suction and dried, giving 320 mg of the coup-ling product (89%); MS-FAB (M+H+) = 362.3; Rf (polar method): 1.96 min.
Step 5: Cyclisation to give 3-ettiv1-4-15-(3-fluorobenzylamino)-1,3,4-oxa-diazol-2-y11-2-methvlphenol ("Al") 320 mg of the coupling product from step 4 are stirred at 60 C for 1 hour with 287 mg of mercury(11) acetate in 10 ml of methanol in a screw-lid vial.
The reaction solution is filtered through kieselguhr, rinsed with warm methanol, and the filtrate is evaporated. Purification by column chromatog-raphy on silica gel (heptane/EA) gives 186 mg of 3-ethy1-4-[5-(3-fluoro-benzylamino)-1,3,4-oxadiazol-2-y1]-2-methylphenol as solid (64%) -N---N

OH "A1" ;
MS-FAB (M+H ) = 328.2; Rf (polar method): 2.00 min.
Compounds A2 and A3 can be prepared by this method using 1-isothio-cyanatomethy1-3-methoxybenzene or 14(R)-1-isothiocyanatoethyl)-3-methoxybenzene respectively in step 4.
Compound Name and/or structure MS-FAB
No. (M+H ) /
Rf value 3-Ethy1-4-[5-(3-methoxybenzylamino)-1,3,4- 340.1 /
oxadiazol-2-y1]-2-rnethylphenol 1.96 (polar) N¨N

OH
1H-NMR (400 MHz, DMSO-d6) 5 [PPrn] 9.88 (1H, s, br), 8.21 (1H, t, J =
6.3 Hz), 7.33 (1H, d, J = 8.5 Hz), 7.27 (1H, t, J = 8.1 Hz), 6.94-6.97 (2H, m), 6.84 (1H, dd, J = 8.2 Hz, J = 2.6 Hz), 6.78 (1H, d, J = 8.5 Hz), 4.39 (2H, d, J = 6.3 Hz), 3.75 (3H, s), 2.93 (2H, q, J = 7.4 Hz), 2.16 (3H, s), 1.07 (3H, t, J = 7.4 Hz) "A3" 3-Ethyl-4-{5-[(R)-1-(3-methoxyphenypethylaminol-354.1 /
1,3,4-oxacliazol-2-y1}-2-methylphenol 2.03 (polar) = -43-O
N----N

OH
Method 2: (compound "A6") \O 0 1.
OH N-N
H
R' NN
Hg(II), Me0H, 80 C 0 it /
c=¨N
H
R' N-1,1 HO /
ON
Preparation of 2,3-difluoro-4-1.5-(3-fluorobenzvlamino)-1,3,4-oxadiazol-2-vIlphenol ("A6") Step 1: Coupling 500 mg of 2,3-difluoro-4-methoxybenzoic acid, 611 mg of DAPECI, 431 mg of HOBT hydrate and 530 mg of 4-(3-fluorobenzyI)-3-thiosemi-carbazide are dissolved in 5 ml of DMF in a screw-lid vial and stirred overnight at RT. The reaction mixture is poured onto water, the deposited precipitate is filtered off, rinsed with water and dried, giving 772 mg of ' WO 2010/020305 =
coupling product (yield: 79%); MS-FAB (M+H+) = 370.2. Rf (polar method):
2.04 min.
Step 2: Cyclisation to give 5-(2,3-difluoro-4-methoxyphenyI)-1,3,4-oxa-diazol-2-v11-(3-fluorobenzynamine 772 mg of the coupling product from step 1 are stirred at 60 C for 1 hour with 666 mg of mercury(II) acetate in 20 ml of methanol in a screw-lid vial.
The reaction solution is filtered through kieselguhr, rinsed with warm methanol, and the filtrate is evaporated, giving 650 mg of 5-(2,3-difluoro-4-methoxypheny1)-1,3,4-oxadiazol-2-y1]-(3-fluorobenzyl)amine as colourless solid (92%); MS-FAB (M+H+) = 336.2; Rf (polar method): 2.12 min.
Step 3: 2,3-Difluoro-4-15-(3-fluorobenzvlamino2-1,3,4-oxadiazol-2-Aphenol 0.74 ml of BBr3 is added at 0 C to 650 mg of 5-(2,3-difluoro-4-methoxy-pheny1)-1,3,4-oxadiazol-2-y1]-(3-fluorobenzypamine dissolved in 50 ml of DCM in a 100 ml round-bottomed flask, and the mixture is stirred overnight at RT. In order to complete the reaction, a further 0.50 ml of BBr3 are then added, and the mixture is stirred for a further day. 3 ml of methanol are carefully added to the reaction solution at 0 C, and the mixture is evapo-rated in a rotary evaporator. Methanol is again added, and the mixture is again evaporated in vacuo. This operation is repeated a third time. The residue is adjusted to pH 6-7 using sodium hydrogencarbonate solution, and the resultant solid is filtered off with suction. Purification by prep.
HPLC on silica gel RP18 (acetonitrile, water) gives 65 mg of 2,3-difluoro-4-[5-(3-fluorobenzylamino)-1,3,4-oxadiazol-2-yl]phenol "A6") (10.4%); MS-FAB (M+H+) = 322.1; Rf (polar method): 1.86 min.

. WO 2010/020305 . - 45 -Method 3: (compound A5) __________________________________________________ 0 H
li N OH N N¨N
H ____ R R 11 R' S
N,N
Hg(II), Me0H, 80 C HO ---- 1 \ ________________________________________ N O'NN

R' Preparation of 6-15-(3-fluorobenzylamino)-1,3,4-oxadiazol-2-vIlpyridin-3-ol ("A5") Step 1: Coupling 500 mg of 5-hydroxypyridine-2-carboxylic acid, 827 mg of DAPECI, 583 mg of HOBT hydrate and 716 mg of 4-(3-fluorobenzyI)-3-thiosemi-carbazide are dissolved in 5 ml of DMF in a screw-lid vial and stirred overnight at RT. The reaction mixture is poured onto water, and with the aqueous phase is extracted with EA. The separated-off organic phase is dried, evaporated to about 50 ml, and heptane is added until a tacky precipitate separates off. A solution is decanted off from this precipitate, heptane is added and decanted off again. Drying gives 544 mg of a reddish oil (purity 75%, yield 47%), which is used for the next step without further purification. MS-FAB (M+H+) = 321.2. Rf (polar method): 1.70 min.
Step 2: Cyclisation to give 6-15-(3-fluorobenzylamino)-1,3,4-oxadiazol-2-ylk pyridin-3-ol 544 mg of the coupling product from step 1 are stirred at 80 C for 2 hour with 312 mg of mercury(11) acetate in 15 ml of methanol in a screw-lid vial.
The reaction solution is filtered through kieselguhr, rinsed with warm methanol, and the filtrate is evaporated. Purification by prep. HPLC on sil-ica gel RP18 (eluent: acetonitrile, water) gives 54 mg of 6-[5-(3-fluoro-benzylamino)-1,3,4-oxadiazo1-2-yl]pyridin-3-ol as solid (16%); MS-FAB
(M+H+) = 287.1; Rf (polar method): 1.55 min;
1H-NMR (400 MHz, DMSO-d6) 6 [ppm] 8.36 (1H, t, J = 6.3 Hz), 8.18 (1H, d, J = 2.8), 7.81 (1H, d, J = 8.6 Hz), 7.35-7.43 (1H, m), 7.29 (1H, dd, J = 8.6 Hz, J = 2.8 Hz), 7.16-7.24 (2H, m), 7.10 (1H, "pseudo"dt, J = 8.6 Hz, J =
2.5 Hz), 4.46 (2H, d, J = 6.3 Hz).
Method 4: (compound A4) BrCN, . 0 N ¨NH2 NaHCO3, RT /1%1¨N
HO
__,.. HOW 1 R H R
Preparation of 4-15-amino-1,3,4-oxadiazol-2-0-3-ethyl-2-methylphenol ("A4"):
196 mg of cyanogen bromide are added dropwise to a solution of 300 mg of 2-ethyl-4-hydroxy-3-methylbenzohydrazide in 50 ml of water, 130 mg of sodium hydrogencarbonate and 4 ml of DMF. A gas forms and a precipi-tate deposits. The latter is filtered off with suction and purified by column chromatography on silica gel, giving 40 mg of 4-(5-amino-1,3,4-oxadiazol-2-y1)-3-ethyl-2-methylphenol as colourless powder; MS-FAB (M+H+) = 220;
Rf (polar method): 1.43 min;
1H-NMR (400 MHz, DMSO-c16) 6 [PPm] 9.87 (1H, s, br), 7.30 (1H, d, J =
8.5 Hz), 7.01 (2H, s, br), 6.77 (1H, d, J = 8.5 Hz), 2.93 (2H, q, J = 7.4 Hz), 1.08 (3H, t, J = 7.4 Hz).

Pharmacological data Table 1 Compound Target Inhibition No. IC50 (enzyme) "Al" SGK1 A

GSK3-beta A

GSK3-beta B

GSK3-beta A

IC50: 1 nM ¨ 0.1 [LM = A
0.1 [tM -10 [tM = B
> 10 [tM =C

The following examples relate to pharmaceutical compositions:
Example A: Injection vials A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogenphosphate in 3 I of bid istilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile condi-tions. Each injection vial contains 5 mg of active ingredient.
Example B: Suppositories A mixture of 20 g of an active ingredient according to the invention with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Example C: Solution A solution is prepared from 1 g of an active ingredient according to the invention, 9.38 g of NaH2PO4 = 2 H20, 28.48 g of Na2HPO4 12 H20 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 land sterilised by irradia-tion. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
Example E: Tablets A mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give , - 49 -tablets in a conventional manner in such a way that each tablet contains mg of active ingredient.
Example F: Dragees Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga-canth and dye.

10 Example G: Capsules 2 kg of active ingredient are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.
Example H: Ampoules A solution of 1 kg of an active ingredient according to the invention in 60 I
of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims (9)

CLAIMS:

1. A compound which is or pharmaceutically usable salt, solvate, or steroisomer thereof, or a mixture thereof in any ratio.

2. A pharmaceutical composition comprising at least one compound according to claim 1, or pharmaceutically usable salt, solvate, or stereoisomer thereof, or mixture thereof in any ratio, and optionally one or more excipients and/or adjuvants.

3. Use of compound according to claim 1, or pharmaceutically usable salt, solvate or stereoisomer thereof, or mixture thereof in any ratio, for the preparation of a medicament for the treatment or prevention of at least one diabetes, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertonia, cardiovascular diseases, kidney diseases, fibroses, inflammatory processes, cancer, tumour cells, tumour metastases, coagulopathies, neuronal excitability, glaucoma, cataract, bacterial infections, in anti-infection therapy, for increasing learning ability and attention, cell ageing, stress and tinnitus.

4. Use according to claim 3, where diabetes is diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and/or microangiopathy.

5. Use according to claim 3, where cardiovascular diseases are cardiac fibroses after myocardial infarction, cardiac hypertrophy, cardiac insufficiency and/or arteriosclerosis.

6. Use according to claim 3, where kidney diseases are glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and/or electrolyte excretion disorder.

7. Use according claim 3, where fibroses and inflammatory processes are liver cirrhosis, pulmonary fibrosis, fibrosing pancreatitis, rheumatism and arthroses, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scarring and/or Alzheimer's disease.

8. A pharmaceutical composition comprising at least one compound according to claim 1 or pharmaceutically usable salt, solvate, or stereoisomer thereof, or including mixture thereof in any ratio, and at least one further medicament active ingredient.

9. Set (kit) consisting of separate packs of (a) a compound according to claim 1 or pharmaceutically usable salt, solvate, or stereoisomer thereof, or mixture thereof in any ratio, and (b) a further medicament active ingredient.